Process for the preparation of 9-substituted guanine derivatives

ABSTRACT

A process for the preparation of 9-substituted quanine derivatives of general formula (I), in which R is C 1  -C 4  -alkyl optionally substituted with one or more hydroxy groups, or R is (α), benzyl, ribosyl, 2&#39;-deoxyribosyl or (CH 2 ) n  -OR 1  where n is 1 or 2, and R 1  is CH 2  CH 2  OH or (β) or salts thereof, in which a 1-substituted5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide of general formula (III), where R has the same meaning as in formula (I), is cyclized: a) by treatment with a heavy metal salt of the group of Cu-, Ag-, Pb- and Hg-salts in an aqueous alkaline medium containing at least for equivalents of OH-ions at a temperature form about 0° C. to the reflux temperature, or b) by treatment with a peroxy compound in an aqueous alkaline medium at a temperature of about 0°-30° C., whereafter (I) is isolated by treatment with a acid and, if desired, is converted into a salt. The invention further comprises intermediates for use in the preparation of the above-mentioned compounds.

TECHNICAL FIELD

The present invention relates to a process for the preparation of9-substituted guanine derivatives of the general formula I ##STR1## inwhich R is C₁ -C₄ -alkyl optionally substituted with one or more hydroxygroups, or R is ##STR2## benzyl, ribosyl, 2'-deoxyribosyl or (CH₂)_(n)-OR¹ where n is 1 or 2, and R¹ is CH₂ CH₂ OH or ##STR3## or saltsthereof.

Compounds of this type are therapeutically active compounds having anantiviral activity or are intermediates for the preparation of compoundsof interest in gene technology.

BACKGROUND ART

It is known (J. Org. Chem. 51 1277-1282 (1986)) that guanosine can beprepared from 4-carboxamide-5-amino-1-ribofuranosyl imidazole by aprocess in three steps which involves condensation with carbodiimidederivatives, cyclization with PdO present and treatment with NH₄ OH.This process is not attractive because it requires use of the toxiccompound phosgene to prepare the carbodiimide derivatives, and becausethe cyclization and the subsequent treatment with NH₄ OH take a verylong time.

It is also known that the compound of formula I in which R is H can beprepared by a process in which the compound of formula II ##STR4## isfirst methylated to form the corresponding thiometyl compound which isthen cyclized in alkaline medium (A. Yamazaki, Nucl. Acids. Res., 3,1976, 251-259). This process has the drawback that the toxic and evilswelling methylmercaptane is formed as a by-product, and besides theyield is poor. It is reported in the article that cyclization of thecompound II using the heavy metal salt HgO is not possible.

DISCLOSURE OF THE INVENTION

However, surprisingly we have found that it is possible to carry outcyclization of N¹ -substituted derivatives of compounds of formula IIwithout methylating first and using a heavy metal salt in aqueousalkaline medium or using peroxy compounds.

The process according to the invention is characterised in that a1-substituted 5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide of thegeneral formula III ##STR5## where R has the same meaning as in formulaI is cyclized a) by treatment with a heavy metal salt of the group ofCu-, Ag-, Pb- and Hg-salts in an aqueous alkaline medium containing atleast four equivalents of OH⁻ ions at a temperature from about 0° C. tothe reflux temperature, or

b) by treatment with a peroxy compound in an aqueous alkaline medium ata temperature of about 0°-30° C. in the presence of tungstate ions as acatalyst.

whereafter I is isolated by treatment with acid and, if desired, isconverted into a salt.

The starting compounds of formula III ##STR6## in which R is C₁ -C₄-alkyl optionally substituted with one or more hydroxy groups, or R is##STR7## benzyl, ribosyl, 2'-deoxyribosyl or (CH₂)_(n) -OR¹, where n is1 or 2, and R¹ is CH₂ CH₂ or ##STR8## or salts thereof are novelcompounds, and the invention therefore further comprises these compoundsas intermediates for the preparation of 9-substituted guaninederivatives of formula I.

The starting materials of formula III can be prepared by reaction of1-substituted 5-amino-1H-imidazole-4-carboxamides of the formula IV##STR9## in which R has the same meaning as in formula I and in whichhydroxyl groups, if any, in R may be acylated, with acylisothiocyanateand subsequent hydrolysis to remove the N-acyl group and any other acylgroups.

The compounds of formula IV can be prepared by alkylation of the knowncompound 5-amino-1H-imidazole-4-carboxamide in a known manner.

BEST MODE FOR CARRYING OUT THE INVENTION

The process according to the invention in variant a) is preferablycarried out using a copper salt as the heavy metal salt. Hereby a highyield is obtained with a cheap reagent.

Moreover, the process in variant a) is advantageously carried out in theway that the aqueous alkaline medium is provided with an alkali metalhydroxide, preferably sodium or potassium hydroxide.

The process according to the invention in variant b) is preferablycarried out using hydrogen peroxide as the peroxy compound.

PREPARATION OF STARTING MATERIALS Preparation of5-(N'-benzoylthiocarbamoyl)amino-1-methyl-1H-imidazole-4-carboxamide

5-Amino-1-methyl-1H-imidazole-4-carboxamide (6.5 g, 45 mM) andbenzoylisothiocyanate (7.7 g, 47 mM) were refluxed in acetone (90 ml)for 4 hours under N₂. After cooling in an ice bath the formed productwas filtered off, washed with acetone and dried. Hereby was isolated13.0 g (95%) of the title compound as a white powder, mp 194°-196° C.

5-(N'-benzoylthiocarbamoyl)amino-1-ethyl-1H-imidazole-4-carboxamide wasprepared in a similar manner from 5-amino-1-ethyl-1H-imidazole4-carboxamide, mp. 178°-180° C.

5-(N'-benzoylthiocarbamoyl)amino-1-(1-propyl)-1-H-imidazole-4-carboxamidewas prepared in a similar manner from5-amino-1-(1-propyl)-1-H-imidazole-4-carboxamide, mp. 163°-164° C.

5-(N'-benzoylthiocarbamoyl)amino-1-benzyl-1H-imidazole-4-carboxamide wasprepared in a similar manner from5-amino-1-benzyl-1H-imidazole-4-carboxamide, mp. 181°-182.5° C.

1-[(2-Hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide.

5-Amino-1-[[2-(acetyloxy)ethoxy]methyl]-1H-imidazole-4-carboxamide (44.0g, 182 mM) and benzoylisothiocyanate (29.7 g, 182 mM) were refluxed inacetone (430 ml) for 1 hour. To the resulting solution were addedmethanol (430 ml) and potassium carbonate (14.9 g, 108 mM) dissolved inwater (45 ml) whereafter the mixture was refluxed for 4 hours. Aftercooling to room temperature acetic acid was added to a pH-value of 8.The formed product was filtered off at 0° C., washed and dried. Hereby39.2 g (83%) of the title compound was isolated as a white powder, mp.181°-182° C. (dec.). A sample crystallized from water had mp. 182°-183°C. (dec.). ¹³ C-NMR(DMSO-d₆) δppm: 183.9; 163.7; 134.9; 129.3; 127.9;74.0; 70.4; 59.7.

Calculated for C₈ H₁₃ N₅ O₃ S: C 37.06%, H 5.05%, N 27.01%, S 12.37%

found: C 36.92%, H 5.07%, N 27.30%, S 12.28%.

1-[1,3-Dihydroxy-(2-propyloxy)methyl]-5-(thiocarbamoyl)amino-1-H-imidazole-4-carboxamidewas prepared in a similar manner from5-amino-[1,3-dihydroxy-(2-propyloxy)methyl]-1H-imidazole-4-carboxamide,mp. 185° C. (dec.). ¹³ C-NMR(DMSO-d₆) δppm: 183.8; 163.9; 134.8; 129.2;127.9; 80.2; 73.5; 60.7.

Calculated for C₉ H₁₅ N₅ O₄ S: C 37.36%, H 5.23%, N 24.21%, S 11.08%

found: C 37.34%, H 5.16%, N 23.81%, S 10.76%.

1-[(2-Hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide.

Benzoylchloride (5.9 g, 42 mM) was, under N₂, added dropwise to asolution of ammoniumthiocyanate (3.2 g, 42 mM) in acetone (80 ml) at 25°C. in the course of 5 minutes. After reflux for 15 minutes it was cooledto 20° C., and the formed ammonium chloride was filtered off and washedwith acetone (20 ml).

To the filtrate was added5-amino-1-[[2-(acetyloxy)ethoxy]methyl]-1H-imidazole-4-carboxamide (9.7g, 40 mM). The mixture was refluxed under N₂ for 90 minutes. Thenmethanol (80 ml) and potassium carbonate (5.8 g, 42 mM) dissolved inwater (12 ml) were added and the mixture was refluxed for 8 hours underN₂. Water (70 ml) was added to the hydrolysis mixture, and it wastreated with activated coal at 25° C. The solution was then evaporatedto about 70 ml, and the pH-value adjusted to 7.0 with acetic acid. Aftercooling to 5° C. the resulting product was filtered off, washed withwater and dried. Hereby was isolated 8.0 g (77%) of the title compoundas a white powder, mp. 178°-180° C. (dec.). HPLC indicated >96% purity.

1-[(2-Hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide.

Acetyl chloride (1.6 g, 21 mM) was, under N₂, added dropwise to asolution of ammonium thiocyanate (1.6 g, 21 mM) in acetone (30 ml) at25° C. in the course of 5 minutes. After reflux for 15 minutes it wascooled to 20° C., and the formed ammonium chloride was filtered off andwashed with acetone (10 ml).

To the filtrate was added5amino-1-[[2-(acetyloxy)ethoxy]methyl]-1H-imidazole-4-carboxamide (4.8g, 20 mM). The mixture was refluxed under N₂ for 20 hours. Then methanol(40 ml) and potassium carbonate (5.8 g, 42 mM) dissolved in water (12ml) were added and the mixture was refluxed for 7 hours under N₂. Water(50 ml) was added to the hydrolysis mixture, and it was treated withactivated coal at 25° C. The solution was then evaporated to about 30 mland the pH-value adjusted to 7.0 with acetic acid. After cooling to 5°C. the formed product was filtered off, washed with water and dried.Hereby was isolated 3.2 g (62%) of the title compound as a white powder,mp. 175°-177° C. (dec.). HPLC indicated >94% purity.

1-Methyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide.

5-(N'-benzoylthiocarbamoyl)amino-1-methyl-1H-imidazole-4-carboxamide(12.1 g, 40 mM) was added to a mixture of acetone and methanol (1:1)(200 ml). Potassium carbonate 2.8 g, 20 mM) dissolved in water (12 ml)was added. The reaction mixture was refluxed under N₂ for 6 hourswhereafter acetic acid (2.9 g, 48 mM) was added. After stirring in anice bath the product was filtered off, washed and dried. Hereby wasisolated 7.7 g (96%) of the title compound as a white powder, mp.270°-274° C. (dec.) (the conversion begins at about 220° C.).

A sample crystallized from water melts at 280°-283° C. (dec.) (theconversion begins at about 220° C.). ¹³ C-NMR(DMSO-d₆) δppm: 184.0,163.9; 134.8; 130.2; 127.3; 30.9.

Calculated for C₆ H₉ N₅ OS: C 36.17%, H 4.55%, N 35.16%

found: C 36.06%, H 4.53%, N 35.05%

1-Ethyl-5-(thiocarbamoyl)amino-1H-imidazol-4-carboxamide was prepared ina similar manner from5-(N'-benzoylthiocarbamoyl)amino-1-ethyl-1H-imidazole-4-carboxamide, mp.265°-268° C. (dec.) ¹³ C-NMR(DMSO-d₆) δppm: 183.8; 163.9; 133.8; 129.1;127.8; 39.0; 15.2.

Calculated for C₇ H₁₁ N₅ OS: C 39.42%, H 5.20%, N 32.84%

found: C 39.37%, H 5.19%, N 32.71%

1-(1-propyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide wasprepared in a similar manner from(5-(N'-benzoylthiocarbamoyl)amino-1-(1-propyl-1H-imidazole-4-carboxamide,mp. 197°-198° C. (dec.). ¹³ C-NMR(DMSO-d₆) δppm: 183.8; 163.9; 134.4;129.2; 127.7; 45.7; 22.7; 10.8.

Calculated for C₈ H₁₃ N₅ OS: C 42.27%, H 5.77%, N 30.81%

found: C 42.16%, H 5.84%, N 30.86%

1-Benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide was preparedin a similar manner from5-(N'-benzoythiocarbamoyl)amino-1-benzyl-1-H-imidazole-4-carboxamide,mp. 264°-266° C. (dec.) (the conversion begins at about 205° C. ¹³C-NMR(DMSO-d₆) δppm: 183.8; 163.9; 136.5; 134.5; 129.6; 128.6; 127.7;127.4; 47.6.

Calculated for C₁₂ H₁₃ N₅ OS: C 52.34%, H 4.76%, N 25.44%

found: C 52.31%, H 4.73%, N 25.52%

The following examples illustrate the process according to theinvention. Examples 1-7 illustrate process variant a), and examples 8-12illustrate process variant b).

EXAMPLE 1 9-Methylguanine

1-Methyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (3.98 g, 20mM) was dissolved in 1N sodium hydroxide (160 ml). Copper acetate, H₂ O(4.6 g, 23 mM) was added and the reaction mixture as then refluxed for 1hour. After cooling to 50° C. the formed copper sulphide was filteredoff. The filtrate was acidified with acetic acid to pH 5.0. Theresulting product was filtered off at 25° C. washed with water anddried. Hereby was isolated 3.16 g (96%) of the title compound as a whitepowder, mp. >300° C. ¹³ C-NMR(1N NaOD) δppm: 170.7; 163.6; 154.0, 141.4;120.0; 32.2.

Calculated for C₆ H₇ N₅ O: C 43.63%, H 4.27%, N 42.41%

found: C 43.05%, H 4.20%, N 41.95%

EXAMPLE 2 9-Ethylguanine

9-Ethylguanine was prepared in a similar manner from1-ethyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide, mp. >300° C.

Calculated for C₇ H₉ N₅ O, 1/4H₂ O: C 45.77%, H 5.21%, N 38.13%

found: C 45.52%, H 5.00%, N 38.04%

EXAMPLE 3 9-(1-Propyl)guanine

9-(1-Propyl)guanine was prepared in a similar manner from1-(1-propyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide,mp. >300° C. ¹³ C-NMR(DMSO-d₆) δppm: 156.8; 153.3; 151.0; 137.4; 116.5;44.2; 22.7; 10.8.

Calculated for C₈ H₁₁ N₅ O: C 49.73%, H 5.74%, N 36.25%

found: C 49.50%, H 5.76%, N 36.30%

EXAMPLE 4 9-Benzylguanine

9-Benzylguanine was prepared in a similar manner from1-benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide, mp.305°-308° C. ¹³ C-NMR(DMSO-d₆) δppm: 157.0; 153.8; 151.2; 137.6; 137.3;128.7; 127.6; 127.2; 116.6; 45.9.

Calculated for C₁₂ H₁₁ N₅ O: C 59.74%, H 4.59%, N 29.03%

found C 59.50%, H 4.51%, N 28.91%

EXAMPLE 5a 9-[(2-Hydroxyethoxy)methyl]guanine (Acyclovir)

1-[2-Hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide(10.0 g, 38.6 mM) was added to a suspension of copper sulphate (7.0 g,44 mM) in 6N sodium hydroxide (80 ml) and was stirred at roomtemperature for 4 hours. HPLC indicated 100% yield. After filtration 50%aqueous acetic acid (80 ml) was added to the filtrate. After a briefperiod of reflux the material was cooled to 5° C. The product wasfiltered off and crystallized from water, treatment being made withactivated coal. Hereby was isolated 7.8 g (85%)9-[(2-hydroxyethoxy)methyl] guanine, 3/4 H₂ O (Acyclovir) as a whitepowder. HPLC indicated >99% purity, mp. about 250° C. (dec.) ¹³C-NMR(DMSO-d₆) δppm: 156.8; 153.8; 151.4; 137.8; 116.5; 72.1; 70.4 and59.9.

Calculated for C₈ H₁₁ N₅ O₃, 3/4 H₂ O: C 40.25%, H 5.28%, N 29.34%

found: C 40.39%, H 5.22%, N 29.37%.

EXAMPLE 5b 9-[(2-Hydroxyethoxy)methyl]guanine (Acyclovir).

1-[(2-Hydroxyethoxy)methyl]-5-(thiocarbomoyl)amino-1H-imidazole-4-carboxamide(1.30 g, 5.0 mM) was added to a suspension of copper acetate, H₂ O (1.15g, 5.75 mM) in 1N sodium hydroxide (60 ml) and refluxed for 30 minutes.HPLC indicated 100% yield. After filtration acetic acid (5 ml) was addedto the filtrate, and then heating with activated coal was performed. Thecoal was filtered off, whereafter the material was cooled to 5° C. Theprecipitated product was filtered off, washed with water and dried.Hereby was isolated 0.92 g (77%) of 9-[(2-hydroxyethoxy)methyl]quanine,3/4 H₂ O as a white powder. HPLC indicated >99% purity.

The use of other heavy metal salts and varying amounts of sodiumhydroxide in the process of example 5 is illustrated by the followingtable.

    ______________________________________                                        Preparation of Acyclovir                                                       ##STR10##                                                                                    Moles                 yield                                                   NaOH/    re-          acc.  iso-                                      Conc.   moles    action                                                                              reaction                                                                             to    lated                             Metal ion                                                                             NaOH    start.   temp. time   HPLC  yield                             moles   N       comp.    °C.                                                                          hours  %     %                                 ______________________________________                                        Cu.sup.++ (1.15)                                                                      0.1      4       100   2      42    --                                Cu.sup.++ (1.15)                                                                      0.1     12       100   1      88    --                                Cu.sup.++ (1.15)                                                                      1.0      6        25   45     94    --                                Cu.sup.++ (1.15)                                                                      1.0      6       100   1      97    --                                Cu.sup.++ (1.15)                                                                      1.0     12       100   0.5    100   77                                Cu.sup.++ (1.15)                                                                      3.0     12        0    45     95    --                                Cu.sup.++ (1.15)                                                                      6.0     12        25   4      100   85                                Cu.sup.++ (1.15)                                                                      6.0     12        25   2      100   84                                Hg.sup.++ (1.15)                                                                      3.0     12       100   0.5    87    --                                Ag.sup.+ (2.30)                                                                       3.0     12       100   2      100   --                                Pb.sup.++ (1.15)                                                                      3.0     12       100   2      26    --                                ______________________________________                                    

EXAMPLE 6 9-[1,3-Dihydroxy-(2-propyloxy)methyl]quanine

1-[1,3-Dihydroxy-(2-propyloxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide(0.58 g, 2.0 mM) was added to a suspension of copper sulphate (0.32 g,2.3 mM) in 3N sodium hydroxide (8 ml) and refluxed for 1 hour. HPLCindicated 100% yield. After filtration 33% aqueous acetic acid (6 ml)was added to the filtrate, and it was refluxed again while being treatedwith activated coal. The coal was filtered off and the solution wascooled to 5° C. Filtration, washing with water and drying resulted in0.33 g (62%) of 9-[1,3-dihydroxy-(2-propyloxy)methyl]quanine, 3/4 H₂ Oas a white powder, mp. about 245° C. (dec.). ¹³ C-NMR(DMSO-d₆) δppm:157.0; 153.9; 151.3; 137.6; 116.3; 79.9; 71.4; 60.8.

Calculated for C₉ H₁₃ H₅ O₄, 3/4 H₂ O: C 40.22%, H 5.43%, N 26.06%

found: C 40.25%, H 5.31%, N 25.58%

EXAMPLE 7 9-β-D-Ribofuranosyl guanine (guanosine)

5-Amino-1-(β-D-ribofuranosyl)-1H-imidazole-4-carboxamide (5.0 g, 19.4mM) and benzoylisothiocyanate (3.3 g, 20 mM) was stirred at roomtemperature in DMF (40 ml) for 1 hour. The solvent was stripped off inwater-jet vacuo. The residue was dissolved in methanol (160 ml) andpotassium carbonate (1.6 g, 11.6 mM) in water (8 ml) was addedwhereafter the mixture was refluxed at 2 hours. After cooling to roomtemperature acetic acid was added to pH 6. The reaction mixture wasevaporated in water-jet vacuo, and the residue was crystallized fromethanol. Hereby was isolated 5.0 g of crude1-(β-D-ribofuranosyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide.HPLC indicated a purity of about 65% (the remaining 35% was essentiallypotassium acetate).

The crude product of1-(β-D-ribofuranosyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide(5.0 g) was added to a suspension of copper sulphate (2.9 g, 18 mM) in3N sodium hydroxide (60 ml) and refluxed for 1 hour. After filtration33% aqueous acetic acid (30 ml) was added to the filtrate and it wasrefluxed again while being treated with activated coal. The coal wasfiltered off, and the solution was cooled to room temperature overnight.Filtration, washing with water and drying gave 2.0 g (65%) of9-β-D-ribofuranosyl guanine, H₂ O (guanosine, H₂ O) as a white powder,mp. 250° C. (dec.). The product had the same physical data as anauthentic sample of guanosine, H₂ O.

EXAMPLE 8 9-(1-Propyl)guanine

1-(1-Propyl)-5-thiocarbamoyl)amino-1H-imidazole-4-carboxamide (1.14 g,5.0 mM) and sodium tungstate (0.2 g) were dissolved in 1N sodiumhydroxide (50 ml) at 0° C. 35% hydrogen peroxide (1.8 ml, 20 mM) inwater (5 ml) was added dropwise at 0°-10° C. in the course of 30minutes. After stirring in an ice bath for 1 hour pH was adjusted to 5with acetic acid. The formed product was filtered off, washed with waterand dried. Hereby was isolated 0.41 g (42%) of the title compound as awhite powder. HPLC indicated >98% purity. The product had the samephysical data as the product of example 3.

EXAMPLE 9 9-Benzylguanine

1-Benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (2.75 g, 10.0mM) and sodium tungstate (0.1 g) were suspended in 6N sodium hydroxide(20 ml) at 5° C. 35% hydrogen peroxide (4.0 ml, 44 mM) was addeddropwise at 5°-15° C. over 30 minutes. Water (60 ml) was added to theresulting reaction mixture. After stirring for 1 hour in an ice bath pHwas adjusted to 5 with hydrochloric acid. The formed product wasfiltered off, washed with water and dried. Hereby was isolated 1.30 g(54%) of the title compound as a white powder. HPLC indicated about 98%purity. The product had the same physical data as the product of example4.

EXAMPLE 10 9-Methylguanine

9-Methylguanine was prepared in a similar manner from1-methyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide. The producthad the same physical data as the product of example 1.

EXAMPLE 11 9-Ethylguanine

9-Ethylguanine was prepared in a similar manner from1-ethyl-5-(thiocarbamoyl)amino-1-imidazole-4-carboxamide. The producthad the same physical data as the product of example 2.

EXAMPLE 12 9-[(2-Hydroxyethoxy)methyl]guanine (Acyclovir)

1-[(2-Hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide(2.59 g, 10.0 mM) and sodium tungstate (0.05 g) were dissolved in 6Nsodium hydroxide (20 ml) at 5° C. 35% hydrogen peroxide (4.0 ml, 44 mM)was added dropwise at 5°-15° C. in the course of 15 minutes. Afterstirring for 15 minutes at 0°-5° C. HPLC indicated 59% yield of thetitle compound. The pH-value of the reaction mixture was adjusted to 5.5with 25% aqueous acetic acid. The resulting product was filtered off,washed with water and dried which gave 1.13 g (50%) of the titlecompound as a white powder. HPLC indicated a purity of about 97%. Theproduct had the same physical data as the product of example 5.

I claim:
 1. A process for the preparation of 9-substituted guaninederivatives of formula I ##STR11## in which R is C₁ -C₄ -alkyl,optionally substituted with one or more hydroxy groups, or R is##STR12## benzyl, ribosyl, 2'-deoxyribosyl or (CH₂)n -OR¹ where n is 1or 2, and R¹ is CH₂ CH₂ OH or ##STR13## and pharmaceutically acceptablesalts thereof, comprising the steps of cyclizing a 1-substituted5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide of formula III##STR14## where R has the same meaning as in formula I a) by treatmentwith a heavy metal salt selected from the group consisting of Cu-, Ag-,Pb- and Hg-salts in an aqueous alkaline medium containing at least fourequivalents of OH⁻ ions at a temperature from about 0° C. to the refluxtemperature, orb) by treatment with a peroxy compound in an aqueousalkaline medium at a temperature of about 0°-30° C., whereafter I isisolated by treatment with acid, and, if desired, is converted into apharmaceutically acceptable salt.
 2. A process as claimed in claim 1 a)wherein the heavy metal salt is a copper salt.
 3. A process as claimedin claim 1, wherein compounds of formula (I) are cyclized by treatmentwith a peroxy compound in an aqueous alkaline medium at a temperature ofabout 0°-30° C., wherein the peroxy compound is hydrogen peroxide, andthe cyclization is carried out in the presence of tungstate ions ascatalyst.